Nicotine is a major agent of abuse; its consumption is often anecdotally associated with stress and may constitute a means for coping with stress. Investigating the brain neurochemistry that underlies the effect(s) of nicotine on the brain response to stress, can clarify and help establish a mechanistic basis for observations relating nicotine consumption to stress. This can be accomplished with a well defined and readily quantified system that responds to nicotine and stress. The hypothalamic-adenohypophyseal unit that regulates the secretion of prolactin (Prl) and adrenocorticotropin (ACTH) meets these criteria for a model system. Our preliminary data indicates that the elevation of plasma Prl and ACTH levels conventionally produced by acute restraint stress is significantly attenuated by chronic exposure to nicotine. Thus, the initial focus of this proposal is to study the effects of both acute and chronic exposure to nicotine in vivo on the regulation of Prl and ACTH secretion in both non-stressed and stressed rat models. With these relationships established, we will test the related hypotheses that: (1) exposure to nicotine alters the cholinergic regulation of adenohypophyseal ACTH secretion through effects on the release of corticotropin-releasing-factor (CRF); (2) chronic exposure to nicotine attenuates the plasma ACTH response to acute stress as a result of diminished cholinergic stimulation of CRF release in response to stress and/or diminished CRF responsiveness to the cholinergic stimulation of stress. These hypotheses are supported by recent evidence that chronic exposure to nicotine induces behavioral tolerance that is associated with changes in cholinergic-nicotinic receptor number. Investigation of these hypotheses will involve selective receptor and ligand antagonists in vivo, and the measurement of hypothalamic and pituitary secretions in vitro by incubation of explants. The insights gained from this work will help focus future studies to explore the effects of chronic nicotine exposure at the cellular level within the paraventricular nucleus.